Research on serotonin and suicidal behavior: neuroendocrine and molecular approaches

We carried out two studies to test the hypothesis that altered central serotonergic function, as assessed by lower prolactin (PRL) response to fenfluramine (D-FEN), is more closely associated with suicidal behavior than a particular psychiatric diagnosis. A D-FEN test was performed in 85 major depressed inpatients, 33 schizophrenic inpatients, and 18 healthy controls. We showed that PRL response to D-FEN is a marker of suicidality, regardless of psychiatric disorder. We then examined the association en the serotonin (5-hydroxytryptamine) receptor 5-HT(2A) gene polymorphism (T102C) and suicide in a sample of Brazilian psychiatric inpatients (95 with schizophrenia, 78 with major depression) and 52 healthy controls. No differences were found in genotypic frequencies across patients and controls. Overall, no differences were found between patients with (n=66) and without (n=107) a history of suicide attempt. We also compared patients with a history of severe suicide attempts (lethality>3; n=32) and patients without such a history (n=107), but they did not exhibit different genotypic frequencies either. These results show thai the 5-HT(2A) gene polymorphism (T102C) may not be involved in the genetic susceptibility to suicidal behavior.     

Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.     

Combined action of the ACE D- and the G-protein beta3 T-allele in major depression: a possible link to cardiovascular disease?

Although it is well established that depression is a major risk factor for the development of coronary artery disease and that cerebrovascular disease can be a major contributing factor for the development of depression, the information about the interplay between the central nervous system and cardiovascular disease is still limited. We investigated the angiotensin I converting enzyme (ACE) ID and the G-protein beta3-subunit (Gbeta3) C825T polymorphism in 201 patients with unipolar major depression and 161 ethnically and age-matched controls. Both gene variants have earlier been associated with either cardiovascular disease or affective disorders, making them good candidates for a combined analysis. We found a significant increase in the Gbeta3 T allele (OR = 1.61, 95% CI 1.17-2.2, P = 0.0035) and a marginal altered genotype distribution of the ACE ID polymorphism with decrease in the II genotypes (chi(2) = 6.43, df=3, P = 0.04) in the patients' group. Analysing the data for both genes we found that the combined actions of ACE and Gbeta3 genotypes accumulate in carriers of the ACE D allele (ID and DD) and Gbeta3 TT homozygotes with ID/DD-TT carriers showing a more than five-fold increase in risk for major depression (crude OR = 5.83, 95% CI 1.99-17.08, P = 0.0002). As our study was carried out with depressive patients without serious cardiac impairment at the time of the investigation, we are presently unable to predict whether this combined action of the ACE ID/DD-Gbeta3 TT genotype is increasing the risk for both disorders. Nevertheless our study reports for the first time that the same allelic combination of two genes that have been shown to increase the risk for myocardial infarction (Naber et al, 2000) increase the vulnerability for depressive disorder.     

Common genetic factors for depression and cardiovascular disease

There is increasing knowledge regarding the considerable comorbidity between depression and cardiovascular disease, which are two of the most common disorders in developed countries. The associated vulnerability is not unidirectional, as the presence of cardiovascular disease can also influence mood states. Although this may be the result of psychological factors, common biological mechanisms, including genetic ones, are thought to be responsible for this interaction; we can thus question whether variations in genes could be predisposing factors. Regarding the multiple interactions in the mechanisms between depression and cardiovascular system disorders, e.g., dysfunctions in the hypothalamic-pituitary-adrenocortical and sympathoadrenal axis and the response to stress, the importance of the serotonergic and immune systems, or the impact on the renin-angiotensin system, several candidate genes are being investigated. However, despite the interest in unraveling the potential susceptibility genes for both disorders, most available studies have so far dealt with the impact of polymorphisms in relation to either depression or cardiovascular disease. A few recent studies have now examined the effects of gene-gene or gene-environment interactions, and are investigating the impact of "depression-related" variants on cardiac response to stress. The first promising results were obtained with the serotonin transporter, and it may be hypothesized that this polymorphism interacts via the impact of the S allele on depression and via the effect of the L allele on platelet activation. However, the role played by various other candidate genes remains to be determined, especially regarding the question as to whether they are indicative of common pathophysiological mechanisms, or for identifying a subgroup of patients with somatic disorders that are more closely related to psychiatric symptoms.     

Association study of angiotensin-converting enzyme gene polymorphism with schizophrenia and polydipsia.

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system and can modulate dopamine turnover in the midbrain. Previous studies have revealed changes in the central ACE levels for schizophrenic patients, possibly related to the polydipsia commonly demonstrated for chronic schizophrenia. An insertion (I)/deletion (D) polymorphism of the ACE gene has been associated with ACE levels. Therefore, we elected to investigate the ACE I/D polymorphism for 124 schizophrenic patients and 117 control subjects. No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and schizophrenic patients. The ACE genotypes were not associated with onset age or psychiatric symptoms for the schizophrenic cases. A modest association was revealed for this ACE polymorphism and polydipsia diagnosis for these patients. Using bearers of the D allele as baseline, the ratio for I/I homozygote was 2.31 (95% CI 0.95-5.65). This association needs further replication as it may have implications for the pathogenesis and the treatment of polydipsia for schizophrenic patients.     

Interaction between the serotonergic system and HPA and HPT axes in patients with major depression: implications for pathogenesis of suicidal behavior

Disturbances in the serotonin (5-hydroxytryptamine, 5-HT) system constitute the neurobiological abnormality most consistently associated with suicide. This abnormality could be a marker of vulnerability predisposing individuals to auto-aggressive and impulsive behavior. However, other abnormalities, such as hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, have also been described in suicide victims. While inhibitory effects of adrenocorticosteroids on 5-HT(1A) receptor function have been shown in animals, HPA axis hyperactivity does not seem to be responsible for the reduced 5-HT activity found in depressed patients with a history of suicidal behavior. On the other hand, hypothalamic-pituitarythyroid (HPT) axis dysfunction, frequently observed in depression, may represent a compensatory response to reduced central 5-HT neurotransmission. Moreover, in depressed patients with a history of suicidal behavior, the absence of a functional link between HPT and dopamine activity at the hypothalamic level may be implicated in the pathophysiology of suicidal behavior. Future research is needed to determine why compensatory mechanisms are not efficient in patients with suicidal behavior.     

高血压性脑出血与血管紧张素转换酶基因多态性及血清水平关系的研究

目的：探讨原发性高血压（EH）,高血压性脑出血（CH）与血管紧张素转换酶（ACE）基因I／D多态性及血清ACE水平的相互关系。方法：对正常人（NC组）29例,EH组28例和CH组31例提取白细胞DNA,检测ACE基因型,等位基因和血清水平。结果：88例中不同ACE基因型血清ACE水平有显著性差异（DD＞ID＞II,P＜0．01）,EH组DD基因及D基因频率与NC组比较无显著性差异（P＜0．05）,CH组血清ACE水平和D基因频率显著高于NC组及EH组（P＜0．01）,其DD型的血清ACE水平也高于后二者（P＜0．05）,结论：ACE基因多态性及其血清水平与EH无关,而与CH呈正相关,D基因可能为高血压病患者脑出血发病的相对危险因素。     

Pathophysiology of depression and mechanisms of treatment

Major depression is a serious disorder of enormous sociological and clinical relevance. The discovery of antidepressant drugs in the 1950s led to the first biochemical hypothesis of depression, which suggested that an impairment in central monoaminergic function was the major lesion underlying the disorder. Basic research in all fields of neuroscience (including genetics) and the discovery of new antidepressant drugs have revolutionized our understanding of the mechanisms underlying depression and drug action. There is no doubt that the monoaminergic system is one of the cornerstones of these mechanisms, but multiple interactions with other brain systems and the regulation of central nervous system function must also be taken into account In spite of all the progress achieved so far, we must be aware that many open questions remain to be resolved in the future.     

Renin-angiotensin-system gene polymorphisms and depression

Given the abundance of the renin-angiotensin system (RAS) components in the brain, their importance in behavior and cognition, and the data that implicates them in the etiology and treatment of depression, it is possible that those RAS gene polymorphisms associated with increased RAS activity may also be associated with depression. The frequencies of common polymorphisms of genes encoding for components of the RAS, namely angiotensinogen (M235T), angiotensin converting enzyme (ACE) (insertion, I; deletion, D), angiotensin receptor type I (A1166C), and angiotensin receptor type II (C3123A) were determined in DNA extracted from buccal cells from a Lebanese population of 132 depressed patients and their first-degree relative case-controls. The angiotensin receptor type 1 (A1166C) CC genotype was significantly associated with depression (p=0.036). None of the other common RAS-associated polymorphisms were significantly associated. The results support the hypothesis that increased RAS activity may increase relative risk of depression in that the angiotensin receptor type 1 (A1166C) CC genotype is associated with increased responsiveness to angiotensin II.     

Treatment of affective disorders in cardiac disease

Patients with cardiovascular disease (CVD) commonly have syndromal major depression, and depression has been associated with an increased risk of morbidity and mortality. Prevalence of depression is between 17% and 47% in CVD patients. Pharmacologic and psychotherapeutic interventions have long been studied, and in general are safe and somewhat efficacious in decreasing depressive symptoms in patients with CVD. The impact on cardiac outcomes remains unclear. The evidence from randomized controlled clinical trials indicates that antidepressants, especially selective serotonin uptake inhibitors, are overwhelmingly safe, and likely to be effective in the treatment of depression in patients with CVD. This review describes the prevalence of depression in patients with CVD, the physiological links between depression and CVD, the treatment options for affective disorders, and the clinical trials that demonstrate efficacy and safety of antidepressant medications and psychotherapy in this patient population. Great progress has been made in understanding potential mediators between major depressive disorder and CVD—both health behaviors and shared biological risks such as inflammation.     

Bipolar disorder--methodological problems and future perspectives

Since its "rebirth" in 1966, bipolar disorder (BPD) has rapidly come to occupy a central position in the research and treatment of mood disorders. Compared with major depressive disorder (MDD), BPD is a more serious condition, characterized by much more frequent recurrence, more complex comorbidity, and higher mortality. One major problem is the lack of valid definitions in adult and in child psychiatry; the current definitions are unsatisfactory, and heavily favor an overdiagnosis of MDD. Biological research is partially based on those definitions, which have a short half-life. An additional, dimensional, approach, quantifying hypomania, depression, and anxiety by self-assessment and symptom checklists is recommended. A further, related problem is the early recognition of the onset of BPD, especially in adolescence, and the identification of correlates in childhood. Early and timely diagnosis of BPD is necessary to enable prompt intervention and secondary prevention of the disorder. The paper describes the current status and future directions of developing clinical concepts of bipolarity.     

Experimental animal models for the simulation of depression and anxiety

An impressive number of animal models to assess depression and anxiety are available today. However, the relationship between these models and the clinical syndromes of depression and anxiety is not always clear. Since human anxiety disorders represent a multifactorial phenomenon frequently comorbid with major depression and/or other psychiatric problems, the chance of creating animal models which consistently reflect the human situation is quite poor. When using experimental models to understand homologies between animal and human behavior, we have to consider the context in which an animal is investigated, and both the functional significance and relevance of the behavioral parameters that are quantified. Moreover, gender and interindividual and interspecies variabilities in behavioral responses to the test situation and in the sensitivity to pharmacological treatments are potential sources for confounding results. In the past, these aspects have been often neglected in preclinical approaches to behavioral pharmacology and psychopharmacology. A pragmatic approach of combined preclinical and clinical efforts is necessary to imitate one or more aspects relevant to pathological anxiety disorders and depression. The resulting models may identify central nervous processes regulating defined behavioral output, with the potential to develop more effective treatments.     

遗忘型轻度认知障碍与血管紧张素转换酶的基因多态性和血清水平关系的研究

目的 探讨遗忘型轻度认知障碍(aMCI)与血管紧张素转换酶(ACE)基因插入和缺失(I/D)多态性及血清ACE活力水平的关系.方法 对符合美国Meyo诊所Petersen等制定的aMCI诊断标准的90例aMCI患者(aMC[组)及90名与aMCI组相匹配正常对照者(对照组)进行神经认知功能评估,并应用聚合酶链反应检测ACE基因I/D多态性,用紫外分光光度法检测血清ACE活力水平.结果 (1)aMCI组的各项神经认知测试成绩均差于对照组(P<0.01).(2)aMCI组ACE基因型(χ2=1.510)及等位基因频率(χ2=6.945)与对照组的差异均有统计学意义(P<0.01),其中aMCI组DD基因型(23%)及D等位基因频率(57%)高于对照组(分别为16%和43%).(3)两组DD基因型(n=35)及DI基因趔(n=109)者的听觉词语记忆、符号数宁转换测试、复杂图形及类别词语流畅性得分低于Ⅱ基因型者(n=36;均P<0.05-0.01).(4)aMCI组(F=7.491)和对照组(F=4.970)ACE基因型各亚组问血清ACE活力水平的差异均有统计学意义(P<0.01),两组ACE活力水平均为DD型组>DI型组>II型组.(5)aMCI组血清ACE活力与听觉词语记忆测试的延迟回忆得分呈负相关(r=-0.249,P<0.05).结论 D等位基因可能为aMCI的发病危险因子,其调控的血清ACE高活力水平与aMCI患者情节记忆损害有关.     

Association of Angiotensin-converting enzyme insertion(I)/deletion (D) genotype in Alzheimer's disease patients of north Indian population

Several lines of evidence support for the role of angiotensin-converting enzyme (ACE) in Alzheimer's disease (AD) patients. Most human genetic studies have focussed on ACE insertion (I)/deletion (D) polymorphism and have yielded conflicting results. We have evaluated the association of ACE polymorphism with serum ACE activity in 95 AD patients and 110 healthy controls from north Indian population. In Alzheimer's patients a higher frequency of D allele was detected (I/D ratio 0.53:0.47) compared with the control group (I/D ratio 0.54:0.45), the difference being not statistically significant (p > .05). AD patients were found to be more homozygous for the D allele (26.3%) compared with controls (20.8%). The observed genotype distribution was in agreement with Hardy-Weinberg equilibrium. We observed that the D/D genotype is more in patients with a higher serum ACE activity. The D allele and the D/D genotype in AD patients may influence increased risk of cognitive impairment.     

Common genetic risk factors for psychiatric and simatic disorders

There is increasing knowledge about considerable comorbidity between psychiatric and somatic diseases, questioning whether variations in genes could be predisposing factors for both conditions. With respect to the multiple interactions between brain and body investigations have centered on variants in several candidate genes for proteins that mediate these interactions and therefore also have implications in psychiatric disorders. The available data, although still preliminary and rare, indicate the importance of polymorphic variants in genes coding for the serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT), the 5-HT(2A) receptor, proinflammatory cytokines, and the angiotensin-converting enzyme (ACE) in migraine, fibromyalgia, cardiovascular disorders, and psychiatric conditions. The role played by these various polymorphisms remains to be determined, as does whether they are indicative of common pathophysiological mechanisms or identify a subgroup of patients with somatic disorders that are more closely related to psychiatric symptoms. Nevertheless, they do at least illustrate the potential influence of genetic differences on illness course and treatment outcome, and might be a rational approach to drug development and treatment paradigms.     

5-羟色胺2A受体T102C基因多态性与卒中后抑郁的关联研究

目的 探讨5-羟色胺(5-HT)2A受体T102C基因多态性与卒中后抑郁(PSD)的关系,研究PSD的遗传发病机制.方法 选择珠江医院神经内科自2010年1月至2010年12月收治的汉族住院患者为研究对象,根据有无并发抑郁症将其分为PSD组(97例)及单纯卒中组(72例).采用PCR和限制性片断长度多态性(RFLP)技术测定2组患者5-HT2A受体T102C等位基因频率及基因型.结果 PSD组中突变型C等位基因频率(43.3％)低于单纯脑卒中组(59.0％),突变纯合子C/C基因型频率(20.6％)也低于单纯卒中组(34.7％),差异均有统计学意义(x2=0.179,P=0.004;x2=7.855,P=0.020).结论 5-HT2A受体T102C基因可能是PSD的易感基因,C等位基因是罹患PSD的保护因子.     

Interaction between apolipoprotein-E and angiotensin-converting enzyme genotype in Alzheimer's disease

Both apolipoprotein-E (apo-E) epsilon 4 allele and angiotensin-converting enzyme (ACE) deletion (D) polymorphism have been associated with a high risk for coronary heart disease. Increased frequency of the epsilon 4 allele has also been reported in patients with late-onset of familial and sporadic Alzheimer's disease (AD). The primary aim of this study is to examine the possible relationship between the ACE gene polymorphism and AD. The second aim of this study is to explore the relation of the ACE and apo-E genotypes with AD. Polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and agarose gel electrophoresis techniques were used to determine the apo-E and ACE genotypes. The frequencies of ACE D and ACE insertion (I) allele among AD patients and controls were 55.7 percent versus 44.2 percent and 51.7 versus 48.2 percent, respectively. Apo-E allele frequencies in the AD group for epsilon 2, epsilon 3 and epsilon 4 were, 1.7 percent, 96.5 percent, and 1.7 percent, respectively. The apo-E allele frequencies of healthy groups for epsilon 2, epsilon 3 and epsilon 4 were 1 percent, 56 percent, and 1.7 percent, respectively. In conclusion ACE D and apo epsilon 4 allele were found to be more frequent in patients with Alzheimer's disease than in the control group.     

The ACE deletion polymorphism is not associated with Parkinson's disease

The deletion allele (D allele) polymorphism in the angiotensin converting enzyme (ACE) gene is associated with increased levels of the neuropeptide substance P in the basal ganglia and substantia nigra. A reduction of substance P levels in the brain occurs in Parkinson's disease (PD) and has been implicated in the pathogenesis of the disease. We investigated the hypothesis that the D allele may be protective towards PD by examining the frequency of the ACE (I/D) polymorphism in 178 PD cases (male:female ratio = 1.4) and 192 controls (male:female ratio = 1.5). ACE (I/D) genotype was determined using polymerase chain reaction and 3% agarose gel electrophoresis. Unadjusted chi-square analysis revealed no significant difference between genotype frequencies (chi2 = 3.30, p > 0.10) or allele frequencies (chi2 = 2.52, p > 0.10) between patient and control groups, although PD patients were less likely to be homozygous (OR = 0.80, 95% CI = 0.49-1.29) or heterozygous (OR = 0.80, 95% CI = 0.59-1.06) for the D allele. A stepwise logistic regression analysis of the ACE deletion and risk factor data confirmed that there was no significant association between the ACE deletion (D allele) polymorphism and PD (OR = 0.62, 95% CI = 0.35-1. 10, p = 0.10). This study does not support the hypothesis that the D allele of the ACE gene confers a protective effect with respect to PD.     

Genetic variants in the angiotensin I-converting-enzyme (ACE) and angiotensin II receptor (AT1) gene and clinical outcome in depression

The insertion/(I)/deletion (D) polymorphism of the angiotensin-converting enzyme gene (ACE) is of increasing interest in etiology and treatment of various neuropsychiatric disorders. The present study aimed to replicate own earlier findings that depressive patients with the ACE D-allele are responding better to treatment with antidepressants than those with the II genotype. We further investigated a common polymorphism (A1166C) in the angiotensin II receptor gene (AT1) to examine a possibly combined influence. A sample of 273 patients with major depression, being treated with different classes of antidepressants, was enrolled in the study. Genotyping was carried out using a polymerase chain reaction and snapshot method, respectively, and the severity of depression was monitored using the HAMD-17 scale before and after 4 weeks of treatment. The ACE II genotypes showed poorer improvement in HAMD-17 scale after 4 weeks of treatment (ANOVA: F=4.49, p=0.01) than carriers with one or two D-alleles. Similarly, more than 70% of the AT1 CC homozygotes had a 50% reduction in the HAMD-17 scale within 4 weeks of treatment. Our data might further suggest that patients with a haplotype combining the CC and DD/ID genotypes respond better to treatment than those with either single allele. These results should however be replicated in future research.